AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Toxicity from coumarins was first noted in animals. Livestock were difficult to feed on North American prairies until the introduction of melilots, or sweet clovers (ie, Melilotus alba, Melilotus officinalis), from Europe in the early 1900s.

In 1924, Schofield noted cattle in Alberta that were fed moldy spoiled sweet clover hay were dying from a previously undescribed hemorrhagic disorder; properly cured hay appeared harmless. Bishydroxycoumarin, the active ingredient responsible for this hemorrhagic disorder, was discovered in 1939 by Campbell and Link.

Bishydroxycoumarin is formed when fungi in moldy sweet clover oxidize coumarin to 4-hydroxycoumarin, an anticoagulant. In 1940, bishydroxycoumarin was synthesized and used clinically 1 year later as an oral anticoagulant under the American trade name dicumarol.

Coumarin-derivatives possessing a 4-hydroxy group with a carbon at the 3 position of the coumarin-base structure possess anticoagulant activity and are referred to as hydroxycoumarins, which are not present in coumarin itself.

Warfarin (name derived from Wisconsin Alumni Research Foundation and Coumarin) was synthesized and used as a rodenticide for nearly a decade prior to its 1954 introduction into clinical medicine.

Today, the 4-hydroxy coumarins are primarily used as anticoagulants and rodenticides. Second-generation rodenticides (long-acting anticoagulants, such as brodifacoum) are characterized by their clinical effects and very long half-lives.

Coumarin-derived products may be synthesized or obtained from tonka seeds (Dipteryx odorata, Dipteryx oppositifolia). Oral anticoagulants are divided into two groups, hydroxycoumarins (including warfarin) and indanediones.

This chapter focuses on hydroxycoumarins and their anticoagulant effects.

Pathophysiology

Vitamin K is a cofactor required for the postribosomal synthesis of active coagulation factors II, VII, IX, and X, as well as proteins S and C (important modulators of coagulation). Synthesis of these factors involves the carboxylation of specific glutamic acid residues in the liver, a step dependent on reduced vitamin K (vitamin K quinol). In this carboxylation reaction, vitamin K is oxidized to vitamin K 2, 3-epoxide. The 4-hydroxycoumarins block vitamin K 2, 3-epoxide reductase, which is needed for the reduction of vitamin K epoxide back to its active form. Dysfunctional coagulation factors are produced in the absence of reduced vitamin K. Half-lives of clotting factors are as follows:

• Factor II - 60 hours
• Factor VII - 4-6 hours
• Factor IX - 24 hours
• Factor X - 48 -72 hours

The bioavailability of warfarin is nearly complete when administered orally, intramuscularly, intravenously, or rectally. Therefore, orally ingested warfarin is completely absorbed and peak plasma concentrations occur about 3 hours postadministration. Ninety-nine percent is bound to plasma proteins, principally albumin, and distributes into a volume equivalent to the albumin space. Depletion of circulating coagulation factors must occur before any effects are evident. Factor VII has the shortest half-life; factor II has the longest. Clinical effects of a single massive dose of warfarin may begin to be apparent by 24 hours and are maximal by 36-48 hours. The patient may be hypercoagulable for a period of several hours after warfarin ingestion, prior to inhibition of factor production. Duration of action may be as long as 5 days.

Warfarin is metabolized extensively by hepatic microsomal enzymes and undergoes enterohepatic recirculation. Warfarin and its metabolites are excreted in urine and feces.

Long-acting anticoagulants, rodenticides, or superwarfarins (eg, difenacoum, brodifacoum) are 4-hydroxycoumarin derivatives; they are highly lipid-soluble and concentrate in the liver. Superwarfarins have a much longer duration of action than traditional warfarins. After intentional overingestion of superwarfarins, patients may be anticoagulated for weeks to months.

Numerous drug interactions with warfarin exist, both accelerating and inhibiting its metabolism. Lack of attention to possible interactions is a common cause of iatrogenic toxicity.

Drugs that potentiate anticoagulation are allopurinol, amiodarone, anabolic steroids, cephalosporins, cimetidine, cyclic antidepressants, erythromycin, ethanol, fluconazole, ketoconazole, metronidazole, nonsteroidal anti-inflammatory drugs (NSAIDs), omeprazole, sulfonylureas, thyroxine, and trimethoprim-sulfamethoxazole.

Drugs that antagonize anticoagulation are antacids, antihistamines, barbiturates, carbamazepine, corticosteroids, griseofulvin, oral contraceptives, phenytoin, and rifampin.

Frequency

United States

Intentional ingestion of warfarin-containing products is rare; however, excessive anticoagulation and bleeding are not uncommon in patients taking warfarin therapeutically. In 1998, 1658 exposures to warfarin were reported to the American Association of Poison Control Centers (AAPCC). These centers cover approximately 95% of the US population, although reports to the AAPCC underestimate true incidence of exposures and poisonings. Of these exposures, 235 were intentional. Of all warfarin exposures, 47 major outcomes (life-threatening event or resultant disability) and 2 deaths were reported. In the same report, 17,724 exposures to anticoagulant rodenticides were documented; 58 were intentional. A total of 28 major outcomes and 1 death were reported.

Mortality/Morbidity

Bleeding indicates major toxicity of 4-hydroxycoumarins.

• Mucocutaneous, genitourinary, and GI are the most frequent sites of bleeding.
• Serious bleeding includes massive hemorrhage with shock, intracranial bleeding, stroke, and pericardial tamponade.
• Upper airway compromise due to an expanding hematoma also may occur.

Age

• Intentional and chronic ingestions are more common in adolescents and adults than children. Munchausen syndrome or Munchausen syndrome by proxy may present as surreptitious ingestion or administration of one of these compounds by a caretaker.
• Single accidental ingestions are the most common exposures in children younger than 6 years. Such exposures to warfarin or brodifacoum rarely result in clinical toxicity.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Elicit a history of exposure to medicinal hydroxycoumarins or rodenticides.
• History may be difficult to obtain from patients who have ingested hydroxycoumarin products surreptitiously or with suicidal intent.
• Ask the following questions to ascertain specific history:
• • Was ingestion a pharmaceutical or a long-acting rodenticide preparation?
  • Was ingestion intentional or unintentional? (Single unintentional ingestions of warfarin and warfarin-containing rodenticides usually are harmless; however, intentional and large unintentional ingestions of pharmaceutical-grade anticoagulants or rodenticides can produce life-threatening bleeding.)
  • How much was ingested?
  • When did the ingestion occur?
  • Was the ingestion a single acute ingestion or a chronic ingestion?

Physical

Bleeding diathesis does not occur until 24 hours postingestion. Continued re-evaluation for signs of coagulopathy is necessary.

Complications of excessive anticoagulation may occur. Initially, assessment of hemodynamic status and neurologic status are most important.

• Excessive ecchymosis and skin necrosis
• Purpura
• Subconjunctival hemorrhage
• Bleeding gums
• Epistaxis
• Menorrhagia
• Gross hematuria
• Hematomas
• Compartment syndromes
• Immediately life-threatening hemorrhage
• • Massive GI bleeding (eg, hematemesis, melena)
  • Intracranial hemorrhage
  • Upper airway compromise due to expanding hematoma

Causes

Warfarin anticoagulants and the anticoagulant rodenticides (Human toxicity from ingestion of plants and herbal medications is extremely rare.)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Factor X deficiency
Factor V deficiency
Hereditary afibrinogenemia
Congenital dysfibrinogenemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Obtain complete blood count, prothrombin time (PT) (expected to be normal if obtained shortly after ingestion), and International Normalized Ratio (INR).
• • Serial PTs at 24 and 48 hours postingestion should identify patients at risk of coagulopathy
  • The World Health Organization introduced INR in an effort to standardize the results of the PT test. Values of INR are independent of the reagents and methods and, therefore, are comparable between laboratories across the country and abroad. The INR is defined as the normal PT ratio that would result if the World Health Organization's primary international thromboplastin were used to test the patient's sample.

    INR = (Patient PT/ normal PT) ISI

    ISI is the International Sensitivity Index of the thromboplastin used in the local laboratory.

• A high performance liquid chromatographic method can be used to detect and quantify serum levels of the following 5 anticoagulant rodenticides: brodifacoum, bromadiolone, coumatetralyl, difenacoum, and warfarin. Warfarin and superwarfarin levels may be obtained; however, these specialized tests generally are not helpful in the ED setting.
• In cases of surreptitious hydroxycoumarin use, vitamin K-2, -3 epoxide and vitamin K can be measured. Elevated levels of vitamin K-2, -3 epoxide suggest block of reductive step by a hydroxycoumarin.
• Fresh frozen plasma provides active anticoagulation factors in patients with significant active bleeding.
• Type and crossmatch packed red cells in patients with hemodynamic compromise or significant blood loss.

Imaging Studies

• If intracranial hemorrhage is suspected, consider CT scan of the head.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

• Begin supportive care.
• Establish intravenous lines if the patient has evidence of bleeding.
• Infuse crystalloid if any signs of shock are present.

Emergency Department Care

Implement supportive measures for severe or continuous bleeding.

The evaluation of patient with hydroxycoumarin ingestion varies, depending on clinical situation.

Single, small, acute ingestions of warfarin in children are unlikely to result in significant toxicity. Treatment may include only PTs at 24 and 48 hours. Utility of baseline coagulation studies soon after ingestion is probably small. Likewise, single small ingestions of rodenticide anticoagulants are unlikely to result in toxicity.

Patients requiring chronic anticoagulation may be merely observed if their coagulation studies are only moderately elevated and no evidence exists of bleeding or risk of significant trauma that may precipitate bleeding (eg, frequent falls in the nursing home).

Massive ingestions, particularly if intentional and repeated, require more aggressive interventions on initial visit.

• GI decontamination
• • Consider activated charcoal in all large acute ingestions.
  • Consider gastric lavage in massive acute ingestion presenting within 1 hour of ingestion. Carefully consider risks of bleeding from this procedure.
• Bleeding
• • Reverse life-threatening hemorrhage with fresh-frozen plasma (FFP) followed by vitamin K-1.
  • Use packed red blood cells for life-threatening hemorrhage.
• Enhanced elimination
• • Warfarin undergoes enterohepatic recirculation. Multiple dose activated charcoal or cholestyramine may accelerate elimination.
  • Oral phenobarbital (30-60 mg/d) or rifampin (60 mg q12h) enhance hepatic P-450 metabolism of warfarin, decreasing its half-life. Consider only in cases of chronic brodifacoum ingestion refractory to vitamin K replacement.

Consultations

• Regional poison center can assist in management of hydroxycoumarin ingestion.
• A toxicologist, if available, may be of assistance with significant ingestions.
• Discuss cases of iatrogenic overanticoagulation with patient's primary care provider.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

For severe or continued bleeding, only vitamin K-1 (phytonadione) (not any other vitamin K derivatives) can be used as an effective antidote. Usual dose is 5-10 mg administered PO/SC. Intravenous injections, even in emergencies, carry substantial risk of anaphylaxis (fatalities have been reported). Intravenous vitamin K should be used very cautiously in emergent conditions. If immediate hemostatic effect is necessary, adequate concentrations of vitamin K-dependent coagulation factors can be restored by transfusion of fresh frozen plasma (10-20 mL/kg). Since reversal of anticoagulant by vitamin K-1 requires synthesis of fully carboxylated coagulation proteins, significant improvement in homeostasis does not occur for several hours; >24 hours may be needed for maximal effect.

Small ingestions of plant material (equivalent to 10-20 mg warfarin) do not cause serious intoxication, yet repeated or chronic ingestion of even smaller amounts (equivalent to 2 mg/d warfarin) can produce significant anticoagulation.

Drug Category: GI decontaminants

Preferred GI decontamination method when decontamination is desired. Generally mixed and given with a cathartic (eg, 70% sorbitol) except in young pediatric patients in whom electrolyte disturbances may be of concern.

Drug Category: Elimination enhancement

Cholestyramine forms a nonabsorbable complex with bile acids in the intestine that inhibits enterohepatic reuptake of intestinal bile salts. Rifampin is used to speed up metabolism of warfarin by induction of hepatic cytochrome P-450 mixed function oxidases.

Drug Category: Pharmacologic antidote

Promotes liver synthesis of clotting factors that, in turn, inhibit warfarin effects.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit all patients with active bleeding or who have intentionally ingested these drugs. Avoid procedures that can precipitate hemorrhage (eg, nasogastric or endotracheal tubes, arterial punctures/line, central lines) unless necessary.

Further Outpatient Care

• Hemodynamically stable adults who take warfarin therapeutically and who have an excessively elevated PT can be monitored closely as outpatients, provided they are in a safe environment and follow-up is arranged.
• Young children who have accidentally ingested a small number of warfarin tablets or rodenticide pellets can be monitored on an outpatient basis. If concern exists regarding the dose, check PT at 24 and 48 hours.
• Inadvertent exposures in adults without complications can be managed likewise.

Transfer

• Consider for transfer any patient with life-threatening hemorrhage beyond the capabilities of your facility.

Deterrence/Prevention

• For accidental childhood ingestions, remove rodenticide from areas where children have access.

Complications

• Complications of hemorrhagic shock (eg, end-organ ischemia, resulting in myocardial infarction or renal failure)
• Intracranial hemorrhage
• Complications of blood products (eg, infections, transfusion reactions)
• Overcorrection of anticoagulation in a patient with medical indications for anticoagulation

Patient Education

• For excellent patient education resources, visit eMedicine's Poisoning Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Use of IV vitamin K has been associated with fatalities, barring IV administration. Reverse hemorrhagic complications with fresh frozen plasma.
• Vitamin K-3 is not effective; the pharmacy should not substitute it as an equivalent.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Tintinalli J, Krome R, Ruiz E. Emergency Medicine; A Comprehensive Study Guide. 4^th ed. McGraw-Hill; 1995.
• Travis SF, Warfield W, Greenbaum BH, et al. Spontaneous hemorrhage associated with accidental brodifacoum poisoning in a child. J Pediatr. Jun 1993;122(6):982-4. [Medline].
• Whyte AC, Gloer JB, Scott JA, Malloch D. Cercophorins A-C: novel antifungal and cytotoxic metabolites from the coprophilous fungus Cercophora areolata. J Nat Prod. Aug 1996;59(8):765-9. [Medline].
• Williams CA, Goldstone F, Greenham J. Flavonoids, cinnamic acids and coumarins from the different tissues and medicinal preparations of Taraxacum officinale. Phytochemistry. May 1996;42(1):121-7. [Medline].

Article Last Updated: Aug 14, 2008